Method for using a masking agent during laser ablation

ABSTRACT

A method of treating a surface by laser ablation to modify selected regions of the surface, while other regions of the surface not to be substantially ablated are protected from the laser beam by a masking fluid, wherein the masking fluid comprises a solution of a pharmaceutically acceptable pyrido benzoxazine compound or derivative thereof effective as a masking agent.

FIELD OF THE INVENTION

This invention relates generally to laser treatments that use a maskingfluid for selectively mitigating the treatment in regions adjacent thedesired treatment zone.

BACKGROUND ART

The clinical use of lasers has escalated in the last 20 years, inparticular for treating diseases and disorders of the eye. Differentwavelengths of laser light have been used to seal leaky retinal bloodvessels, to remove debris from the posterior capsule of the lens aftercataract surgery, and to correct refractive errors by reshaping thecorneal stroma. The latter has proved to be an increasingly popularoption for correction of refractive error compared to other means ofrefractive error correction such as contact lenses and spectacles. Inaddition to treating uniform refractive errors (myopia, hyperopia,astigmatism) laser vision correction technology has been used to treatcorneal surface irregularities such as scars and various cornealdystrophies. This treatment of irregular corneal surface disorders isreferred to as phototherapeutic keratectomy (PTK) and involves ablatinga protruding region of cornea into a smoother surface.

In order to produce a uniform corneal surface by PTK the lower regionssurrounding the protruding areas of cornea must be filled with asuitable medium, otherwise a uniform laser beam will simply ablate thecurrent pattern further into the cornea. To provide such a medium, amasking fluid of high absorption (and therefore small penetration depth)and moderate viscosity is applied to the cornea, filling in the“valleys” and allowing uniform ablation of the cornea by the laser beam.This results in smoothing out of the irregular corneal surface. Maskingfluids for laser refractive surgery using excimer lasers includebalanced salt solution (BSS) and 0.9% saline solution.

Commercial laser refraction correction techniques have generally reliedon the ultraviolet wavelength range and these have typically beendeveloped using an excimer laser, which has been the mainstay of laserrefractive surgery for several years. The excimer laser requires anargon-fluoride gas mixture as the optical media for the oscillationchamber. Although successful refractive error corrections have been madeusing the excimer laser, there are some problems that are associatedwith the use of gas as an optical medium. In addition, the gas requirescontinual replacement, which results in additional cost as well as arequirement for storage facilities.

These problems have been removed with the development of solid-statelasers, which use crystals as optical media instead of gas. Due to thedifferent optical media used, there is a different wavelength emittedfrom the solid state laser (213 nm) compared to the excimer laser (193nm). As a result, a larger penetration depth is potentially exhibited bythe solid-state laser beam. As proposed in applicant's internationalpatent publication WO 01/58398, this increased penetration depth ispotentially advantageous as problems associated with excess fluid on thecorneal surface during excimer laser surgery may be avoided when using asolid state laser. However, studies have shown that the same maskingfluids used for excimer laser corrective surgery show markedly lesslight absorption when used for the same techniques using solid statelasers. This implies that these masking fluids are not suitable for PTKand another masking fluid is required if this procedure is to beexecuted using a solid-state laser.

SUMMARY OF THE INVENTION

It has been realised in accordance with the invention that certainpyrido benzoxazine compounds and derivatives are effective as maskingagents in PTK and other laser treatments. An exemplary and effectivemasking agent is the derivative ofloxacin, an active ingredient of acommercial anti-bacterial solution used for treatment of the eye.

In accordance with a first aspect of the invention, there is provided amethod of treating a surface by laser ablation to modify selectedregions of the surface, while other regions of the surface not to besubstantially ablated are protected from the laser beam by a maskingfluid, wherein the masking fluid comprises a solution of apharmaceutically acceptable pyrido benzoxazine compound or derivativethereof effective as a masking agent.

The wavelength of the laser beam utilised for the treatment ispreferably 213 nm.

An effective such derivative, especially for a laser beam of 213 nm, isofloxacin, the active component of the commercially availableanti-bacterial solution Ocuflox (Trade Mark). Ofloxacin is of chemicalformula C₁₈H₂₀FN₃O₄, has a molecular weight of 316.37, and has thechemical name9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid.

More generally, the preferred class of masking agents are pyrido[1,2,3-de] [1,4] benzoxazine derivatives having the formula:

wherein X is a halogen atom, R is a hydrogen atom or an alkyl grouphaving from 1 to 6 carbon atoms and Z represents (1) a mono-alkylaminoor di-alkylamino group or (2) a cyclicamino group selected from thegroup consisting of azetidinyl, pyrrolidinyl, piperdinyl, morpholinyl,piperidinyl, homopiperazinyl, thiamorpholinyl and pyrazolidinyl, each ofwhich amino groups may be substituted with a hydroxyl group, an alkylgroup having 1 to 6 carbon atoms, an amino group, a hydroxyalkyl grouphaving 1 to 6 carbon atoms or a mono- or di-alkylamino group having 1 to6 carbon atoms in each alkyl group.

More generally, effective masking agents comprise pyrido benzoxazinecompounds and derivatives as aforedescribed having a structural elementeffective to adequately absorb the laser beam wavelength to an extentsufficient for the compound to be a masking agent.

Preferably, the laser beam employed in the treatment is produced from asolid state laser, eg. a neodymium:YAG laser, and may typically be aselected harmonic of the fundamental laser wavelength produced byfrequency conversion by suitable crystals.

A method to which the invention is advantageously applied isphototherapeutic keratectomy (PTK).

It is now proposed to describe the results by which ofloxacin wasestablished as an effective masking agent for 213 nm laser beam. Lightabsorbent studies were carried out using 213 nm radiation produced asthe fifth harmonic wavelength of the fundamental 1064 nm wavelength ofan Nd:YAG laser, with a pulse duration of 6 ns and repetition rate of 20Hz. The pulse energy of the laser was monitored using an energy detectorand a storage oscilloscope. The energy of the laser was obtained fromthe amplitude of the voltage signal delivered from the detector.

Beer's Law states that if light is passed through solution, energy isattenuated according to the formula:E _(f) =E _(i) e ^(−α) ^(M) ^(Cd)

-   -   Where: α_(M) is the molar absorption coefficient in M⁻¹ cm⁻¹    -    C is the concentration in moles per liter    -    d is the distance in cm    -    E_(f) and E_(i) are the final and initial pulse energies        respectively.

In order to determine the amount of light absorbed (A) by the solutionthe molar absorption co-efficient is found from the gradient of thelog-linear plot of Beer's law.

The absorption coefficient (α cm⁻¹) can then be calculated bymultiplying the molar absorption coefficient by the concentration. Oncethe absorption coefficient is obtained, the penetration depth can becalculated from the reciprocal of this value. The penetration depth (incm) can be used to determine whether the solution will provide enoughabsorbence to be used successfully in a PTK procedure using the 213 nmwavelength.

Ofloxacin is present in the ophthalmic solution Ocuflox (Trade Mark) ata concentration of 3 mg/ml. Measurements were then taken for ofloxacinat dilutions (in purified water) of the regular concentration; 1/100,1/150, 1/200, 1/300, 1/500, 1/750, 1/1000. Readings were taken for BSSmaintaining the same dilutions. By keeping the distance (or depth)constant and by varying the concentration a plot of transmission vs.concentration can be obtained as described previously. Five randomreadings were taken for each dilution and the mean calculated, in orderto reduce the error from inter-pulse variations.

All data was obtained consecutively using the same laser to control forany variation between different lasers. Transmission for BSS andofloxacin solution decreased exponentially with increasingconcentration. These transmission plots were obtained for BSS andofloxacin solutions using identical dilutions. There were no significantdifferences in intra-dilution energy readings.

Data obtained for ofloxacin solution and BSS were plotted and thelog-linear plot of this data used to obtain the absorption coefficient.The data obtained for ofloxacin and BSS both fitted well to anexponential curve (R2=0.9806 and 0.9924 respectively). Ofloxacinexhibited a smaller penetration distance than BSS at the 213 nmwavelength and was comparable to BSS at the 193 nm wavelength (Table 1).BSS showed a noticeable increase in penetration distance using the 213nm wavelength compared to its absorption in the 193 nm wavelength (Table1).

TABLE 1 α Penetration Depth Solution (cm⁻¹) (μm) Ofloxacin 198.6 50.3(as Ocuflox ™) 213 nm BSS 140 72 (as Eye Stream ™) 193 nm BSS 12.42 805(as Eye Stream ™) 213 nm

The results from this study suggest that ofloxacin has maskingproperties that are ideal for use with the 213 nm solid-state laser.When compared to BSS at 213 nm, ofloxacin provides a penetrationdistance that is an order of magnitude shorter. These studies alsoconfirm that BSS does not have the ability to mask 213 nm lightsufficiently for PTK.

In addition, the similar penetration distance to BSS at 193 nm suggeststhat ofloxacin at 213 nm is just as suitable for use as a masking fluid.An essential property of a masking fluid is the ability to absorb therelevant laser light well, which is provided by ofloxacin but not BSS atthe 213 nm wavelength. This absorption is essential for the fluid toshield deeper areas of cornea from ablation whilst the cornealprotuberance is ablated.

Ofloxacin administered as Ocuflox solution has previously been used withthe eye as an anti-bacterial agent and thus is known to have highbiocompatibility, can be used for prolonged periods of time, and isreadily available to clinicians. The realisation of the presentinvention that pyrido benzoxazine compounds such as ofloxacin aresuitable as masking agents in laser ablation procedures on the eyeappears therefore to be an especially convenient outcome. It is furtherknown that the amount of ofloxacin absorbed by the surrounding tissues,as with most topical eye treatments, is a small percentage of the totaldrug delivered. The small amount of the compound actually absorbed bythe cornea suggests that it may be suitable in larger concentrations ina PTK operation.

Ofloxacin fluoresces when the laser beam is incident on it, thusrevealing whether the location of incidence is masked or otherwise. Thiswould be a useful property in PTK.

In a second aspect, the invention provides a method of treating asurface by laser ablation with a 213 nm laser beam to modify selectedregions of the surface, while other regions of the surface not to besubstantially ablated are protected from the laser beam by a maskingfluid, wherein the masking fluid comprises a solution of apharmaceutically acceptable substance having the structural element ofofloxacin that makes it effective as a masking agent for a laser beam of213 nm.

In a third aspect, the invention provides a pharmaceutically acceptablepyrido benzoxazine compound when used as a masking agent in thetreatment of a surface by laser ablation to modify selected regions ofthe surface while other regions of the surface not to be substantiallyablated are protected from the laser beam by the masking agent.

The invention further provides the use of a pharmaceutically acceptablepyrido benzoxazine compound as a masking agent in the treatment of asurface by laser ablation to modify selected regions of the surfacewhile other regions of the surface not to be substantially ablated areprotected from the laser beam by the masking agent.

1. A method of treating a surface by laser ablation with a laser beam tomodify selected regions of the surface, comprising: applying to otherregions of the surface not to be substantially ablated a masking fluidthat comprises a solution of a compound selected from pharmaceuticallyacceptable pyrido benzoxazine compounds and derivatives thereofeffective as a masking agent for said laser beam; and directing saidlaser beam onto said surface to modify said selected regions by laserablation, said other regions being protected from the laser beam by saidmasking fluid thereon.
 2. A method according to claim 1 wherein thelaser beam utilised for the treatment is of wavelength about 213 nm. 3.A method according to claim 2 wherein said solution is of apharmaceutically acceptable pyrido benzoxazine compound or derivativehaving a structural element effective to adequately absorb the laserbeam wavelength to an extent sufficient for the compound to be a maskingagent.
 4. A method according to claim 3, wherein the laser beam employedin the treatment is produced from a solid state laser, being a selectedharmonic of the fundamental laser wavelength produced by frequencyconversion by suitable crystals.
 5. A method according to claim 2wherein said masking fluid is a solution of one or more pyrido[1,2,3-de] [1,4] benzoxazine derivatives effective as a masking agentand having the formula: wherein X is a halogen atom, R is a hydrogenatom or an alkyl group having from 1 to 6 carbon atoms and Z represents(1) a mono-alkylamino or di-alkylamino group or (2) a cyclic amino groupselected from the group consisting of azetidinyl, pyrrolidinyl,piperdinyl, morpholinyl, piperidinyl, homopiperazinyl, thiamorpholinyland pyrazolidinyl, each of which amino groups may be substituted with ahydroxyl group, an alkyl group having 1 to 6 carbon atoms, an aminogroup, a hydroxyalkyl group having 1 to 6 carbon atoms or a mono- ordi-alkylamino group having 1 to 6 carbon atoms in each alkyl group.
 6. Amethod according to claim 5 wherein said masking fluid is a solution ofofloxacin.
 7. A method according to claim 6, wherein the laser beamemployed in the treatment is produced from a solid state laser, being aselected harmonic of the fundamental laser wavelength produced byfrequency conversion by suitable crystals.
 8. A method according toclaim 5, wherein the laser beam employed in the treatment is producedfrom a solid state laser, being a selected harmonic of the fundamentallaser wavelength produced by frequency conversion by suitable crystals.9. A method according to claim 2, wherein the laser beam employed in thetreatment is produced from a solid state laser, being a selectedharmonic of the fundamental laser wavelength produced by frequencyconversion by suitable crystals.
 10. A method according to claim 2,wherein said treatment is phototherapeutic keratectomy (PTK).
 11. Amethod according to claim 2 wherein said masking solution fluoresceswhen the laser beam is incident on it.
 12. A method according to claim 1wherein said solution is of a pharmaceutically acceptable pyridobenzoxazine compound or derivative having a structural element effectiveto adequately absorb the laser beam wavelength to an extent sufficientfor the compound to be a masking agent.
 13. A method according to claim1 wherein said masking fluid is a solution of one or more pyrido[1,2,3-de] [1,4] benzoxazine derivatives effective as a masking agentand having the formula: wherein X is a halogen atom, R is a hydrogenatom or an alkyl group having from 1 to 6 carbon atoms and Z represent(1) a mono-alkylamino or di-alkylamino group or (2) a cyclicamino groupselected from the group consisting of azetidinyl, pyrroddlidinyl,piperdinyl, morpholinyl, piperidinyl, homopiperazinyl, thiamorpholinyland pyrazolidinyl, each of which amino groups may be substituted with ahydroxyl group, an alkyl group having 1 to 6 carbon atoms, an aminogroup, a hydroxyalkyl group having 1 to 6 carbon atoms or a mono- ordi-alkylamino group having 1 to 6 carbon atoms in each alkyl group. 14.A method according to claim 13 wherein said masking fluid is a solutionof ofloxacin.
 15. A method of treating a surface by laser ablation witha 213 nm laser beam to modify selected regions of the surface,comprising: applying to other regions of the surface not to besubstantially ablated a masking fluid that comprises a solution of acompound selected from pharmaceutically acceptable substances having astructural element of ofloxacin that makes it effective as a maskingagent for a laser beam of 213 nm; and directing said laser beam ontosaid surface to modify said selected regions by laser ablation, saidother regions being protected from the laser beam by said masking fluidthereon.
 16. A method according to claim 15, wherein the laser beamemployed in the treatment is produced from a solid state laser, being aselected harmonic of the fundamental laser wavelength produced byfrequency conversion by suitable crystals.
 17. A method according toclaim 16 wherein said treatment is phototherapeutic keratectomy (PTK).18. A method according to claim 15 wherein said treatment isphototherapeutic keratectomy (PTK).
 19. A method according to claim 15wherein said masking solution fluoresces when the laser beam is incidenton it.